Cutaneous melanoma currently shows the fastest progression rate among all cancer types worldwide. According to the International Agency for Research on Cancer (IARC), the number of new melanoma cases rose from 132,600 in 2000 to approximately 330,000 in 2022. ¹ The lifetime risk estimated at 1 in 500 in 1935 is now escalating as melanoma affects approximately 1 in 50 individuals in Western populations. ² Although melanoma accounts for a minority of skin cancers, it is responsible for the majority of skin cancer-related deaths due to its high metastatic potential. ³ With 93 new cases recorded in 2022, malignant melanoma ranks 24th out of all malignancies in Tunisia (age-standardised incidence rate [ASR-W]: 0.45 per 100,000), and with 39 deaths (ASR-W mortality rate: 0.31 per 100,000), it ranks as the 24th most common cause of cancer-related deaths. ⁴ Despite these rates in comparison to high-incidence countries, melanoma is viewed as a disproportionately significant public health concern because of its poor prognosis at advanced stages and its high potential for metastasis.

The first-line treatment for the patients with resectable primary tumours is surgery, followed by therapeutic lymphadenopathy or sentinel node biopsy if required. While surgery remains central for early stages, the introduction of effective and immune-based treatments has significantly improved outcomes for patients with advanced disease. ^{5, 6} In this regard, precise patient classification and staging are essential for guiding therapeutic choices and predicting prognosis. Conventional imaging modalities, including contrast-enhanced computed tomography (CT), are widely used for staging. But because CT is based on morphological criteria, it may fail to detect early metastatic disease. In contrast, 18F-fluorodeoxyglucose positron emission tomography coupled with computed tomography ( ¹⁸F-FDG PET/CT) integrates metabolic and anatomic data in a single acquisition, enabling whole-body assessment for metabolically active lesions. ⁷ Reviews have shown that ¹⁸F-FDG PET/CT achieves higher diagnostic capabilities than CT alone for detecting both nodal and distant metastases, particularly in advanced disease stages. Despite strong evidence in the American Joint Committee on Cancer (AJCC) stages III-IV, the role of ¹⁸F-FDG PET/CT remains less well established in early stages. ⁸ The usefulness of this hybrid modality both in staging and restaging has been shown by observational studies conducted in real-world settings, and it has a significant influence on clinical decision-making at various phases of disease.

In Tunisia, ¹⁸F-FDG PET/CT has only been available since late 2019, and its recent integration represents a significant advance in oncology, including melanoma. The lack of published national data prompted this first Tunisian study to assess its utility in routine clinical practice. Therefore, we aimed to determine its optimal use across different disease stages in light of current treatment options. The objectives of this observational retrospective study were as follows: •

To compare the diagnostic performance of ¹⁸F-FDG PET/CT versus contrast-enhanced CT in the initial staging and restaging of melanoma.

From 51 consecutive patients screened, 23 were included for initial staging and 12 for recurrence work-up. 6 were excluded (6 not included upfront with 2 synchronous neoplasia, 1 ocular melanoma, 3 incomplete records, and 10 excluded after screening) ( Figure 1).

Demographic, clinical and histopathologic data on the included patients are presented in Table 1.

Thirty-five patients were included (20 men and 15 women). Median age at melanoma diagnosis was 60 years (range, 32-83). No treatment occurred between the imaging tests and the reference standard verification. The indication for ¹⁸F-FDG PET/CT was initial staging in 23/35 (65.7%) and restaging in 12/35 (34.3%). A primary cutaneous melanoma was documented in 33/35 (94.3%), while 2/35 (5.7%) had an unknown primary. The lower limb 13/33 (39.4%, 4/9), and the head and neck 11/33 (33.3%, 10/1) were the most affected anatomic sites.

Nodular melanoma accounted for more than half of the cases 19/33 (57.6%, 12/7) and ulceration was present in 22/33 of the patients (66.7%).

According to AJCC, 11/35 (31.4%) were stage I/II (9 staging and 2 restaging), 13/35 (37.1%) stage III (9 staging and 4 restaging), and 11/35 (31.4%) stage IV (5 staging and 6 restaging), indicating a broad disease spectrum across both the staging and restaging cohorts.

Among patients classified as free of nodal or distant metastases by the reference standard, the most frequent alternative findings were benign lymphadenopathy (reactive or inflammatory), postoperative changes, and non-specific pulmonary or hepatic nodules that remained stable on follow-up.

Across the entire cohort, ¹⁸F-FDG PET/CT changed the disease classification in 22/35 patients (62.9%), compared with CT alone. Overall, 14/35 (40.0%) were upstaged, 8/35 (22.9%) were downstaged, and 13/35 (37.1%) showed concordant staging with CT. Collectively, these findings indicate a substantial incremental yield of ¹⁸F-FDG PET/CT over CT for both nodal and distant disease assessment, resulting in frequent stage migration at both initial staging and during evaluation for recurrence.

This retrospective study evaluated the value of ¹⁸F-FDG PET/CT in cutaneous and mucocutaneous melanoma for initial staging and restaging, quantified its diagnostic yield relative to CECT, and assessed its usefulness in treatment planning. The analysis was patient-based and focused on accuracy for nodal and distant disease and on inter-modality concordance in the combined cohort. Because ¹⁸F-FDG PET/CT depicts metabolically active disease rather than relying solely on morphologic change, it was hypothesized to uncover clinically occult metastases and drive stage migration more often than conventional imaging. The study therefore tried to translate the findings into a pragmatic, context-adapted imaging pathway for routine practice.

¹⁸F-FDG PET/CT has a high diagnostic yield in nodal staging and generally outperforms conventional imaging. Dancheva et al. ¹² reported sensitivity and specificity of 84.5% and 98.9% for regional nodal staging with ¹⁸F-FDG PET/CT versus 22.5% and 97.7% for conventional CT and US. In a 250-patient series, Reinhardt et al. showed ¹⁸F-FDG PET/CT to be more accurate than PET or CT alone across clinical contexts, with a smaller advantage in initial staging. ¹³

Gellén et al. observed high diagnostic accuracy across stages (accuracy 91.3% in stages I/II, up to 96.2% in unresectable stage III) and noted that ¹⁸F-FDG PET/CT detected small nodal metastases (8-20 mm) in half of true-positive cases. ¹⁴

These findings align with our cohort: For lymph nodes, ¹⁸F-FDG PET/CT showed higher sensitivity, specificity, and accuracy than CECT: 78.6% vs 64.3% sensitivity, 95.2% vs 66.7% specificity, and 88.6% vs 65.7% accuracy, all at the patient level. Fewer PET/CT false positives than CECT (1 vs 7) and modest reduction in false negatives likely reflect metabolic detection and fewer size-based misclassifications.

Our study’s performance for nodal disease was best in stages III-IV, where specificity reached 100%. While in stage I-II, it showed a strong rule-out performance for occult nodal spread with a 100 sensitivity that should be interpreted cautiously across the small early-stage strata.

Lower sensitivity pooled estimates for nodal metastases were reported in a recent meta-analysis by Zamani-Siahkali et al. ¹⁵ with 10,403 patients (sensitivity of 56% and a specificity of 97%). This limitation is partly explained by the restricted spatial resolution of PET for sub 5 mm lesions. For example, Crippa et al. ¹⁶ reported sensitivity of 83% for nodal lesions more than 5 mm, but only 23% for those less than 5 mm.

Additional corroboration from a Cochrane review ¹¹ shows that in a direct comparison after primary resection, ¹⁸F-FDG PET/CT remains favoured and more sensitive than CT for nodal disease (38% versus 23%) with 100% specificity for both. ¹⁷

Patients with Breslow thickness <1 mm have a very low metastasis risk, making imaging low-yield. ^{23– 25} Sentinel Lymph Node Biopsy (SLNB) remains the most sensitive method for micrometastases and the key prognostic factor when Breslow >1 mm. ^{18– 20 18}F-FDG PET/CT may, however, be useful in stage I/II patients with high-risk features (e.g., T4 or ulceration). ^{18, 19, 21}

The 2024 National Comprehensive Cancer Network (NCCN) guidelines ⁸ are concordant in this context and suggest no additional imaging or SLNB for pT1a without clinical suspicion; from stage IB upward, regional nodal ultrasound is recommended, and if nodes are clinically/radiologically negative, SLNB is preferred for micrometastases and prognostication. ⁸ In our cohort, ¹⁸F-FDG PET/CT correctly identified nodal disease in three patients initially classified N0.

Building on this nodal performance, the clinical question shifts to occult distant spread, where ¹⁸F-FDG PET/CT’s role is particularly relevant. A 2012 meta-analysis (74 studies including 10,528 patients) found that ¹⁸F-FDG PET/CT achieved the highest performance for distant disease (sensitivity 80%, specificity 87%, odds ratio 25), outperforming CT (51%, 69%; OR 2.29) and PET alone (74%, 75%; OR 8.14). ²² Similarly, Dancheva et al. ¹² reported a sensitivity of 100% and a specificity of 98.3% for ¹⁸F-FDG PET/CT, compared with 12.3% and 94.5% respectively, for conventional imaging. In line with these findings, Zamani-Siahkali et al. ¹⁵ reported pooled estimates for distant-metastasis detection of 88% sensitivity and 94% specificity for ¹⁸F-FDG PET/CT.

Our results are consistent with the published literature. For distant disease, the advantage was even greater, with markedly fewer missed metastases and better overall accuracy (92.9% vs 50.0% for sensitivity, 90.5% vs 81.0% for specificity, and 91.4% vs 68.6% for accuracy). These results explain why inter-modality agreement was only fair for nodes (κ = 0.27) and poor for distant sites (κ = 0.16). This poor concordance was largely explained by the broader organ capture of ¹⁸F-FDG PET/CT, which identified numerous extra-visceral metastases missed by CECT and simultaneously reduced false positives in our cohort. Such incremental yield has been repeatedly confirmed in large series, including Reinhardt et al., ¹³ where ¹⁸F-FDG PET/CT correctly staged 97.2% of 250 patients and detected significantly more visceral and non-visceral metastases than CT alone. Similarly, Weber et al. ²³ found ¹⁸F-FDG PET/CT to be significantly more sensitive than ultrasound across per-patient (sensitivity of 71% for ¹⁸F-FDG PET/CT and 48% for US, and specificity of 96% versus 97% respectively), per-examination, and per-lesion analyses, particularly for distant and abdominal metastases. This broader organ detection strengthens the rationale for whole-body ¹⁸F-FDG PET/CT when unsuspected extra-visceral spread would alter management.

Data summarised by Dinnes et al. ¹¹ further support the advantage of ¹⁸F-FDG PET/CT in initial staging: in Veit-Haibach et al. study, ^{17 18}F-FDG PET/CT detected two additional distant metastases over CT (sensitivity 42% vs CT 25% and identical specificity 93%), and in Arrangoiz et al. study ²⁴ (thick, clinically node-negative primaries), ¹⁸F-FDG PET/CT detected all five distant metastases (sensitivity 100% and specificity 94%). Bronstein et al. ²⁵ found that ¹⁸F-FDG PET/CT detects unexpected metastases in a small but significant percentage (12%), and in 6% of scans, unexpected metastases were found in the extremities, areas not typically included in conventional imaging and detected in the whole-body scan of the PET/CT. For intracranial disease, and when suspected, liver, MRI remains the preferred for brain and hepatic metastases respectively. ¹⁶

In stage-stratified analyses of our cohort, diagnostic performance for distant remained robust and stronger than in nodal disease across AJCC groups. In stage I-II, ¹⁸F-FDG PET/CT favoured rule-out with 100% specificity, while in stage III-IV, it provided both rule in and rule out confidence (sensitivity of 90.9% and a specificity of 100%). This suggests that ¹⁸F-FDG PET/CT can confidently exclude metastatic disease even in early-stage patients, and reliably confirm disease in advanced stages.

The 2024 NCCN and the European consensus-based interdisciplinary guidelines recommends whole-body imaging with CT or ¹⁸F-FDG PET/CT for stage III macrometastatic disease and stage IV. It may be considered for poor-prognosis stage IIC and discussed in stage IIIA with micrometastases. ^{8, 26}

Melanoma recurrence is common after resection and reaches up to 30%, particularly in advanced disease, with 50 to 80% relapsing in locoregional disease and up to 95% in the presence of distant metastases. ²⁷ Reported accuracies for ¹⁸F-FDG PET/CT in restaging are high reaching 96% in the prospective diagnostic study by Mijnhout et al., ²⁸ while Agrawal et al. ²⁹ reported accuracies of 92% for regional nodes and 86% for distant disease, confirming ¹⁸F-FDG reliability.

These diagnostic gains translated into meaningful therapeutic impact. In almost half of evaluable patients, management changed after ¹⁸F-FDG PET/CT, most commonly due to the discovery of occult nodal or distant foci that shifted care from local procedures to systemic therapy or clarified equivocal CT findings and prevented unnecessary interventions. This aligns with prior prospective and retrospective work showing that PET-based staging alters treatment plans in a substantial share of melanoma patients, with variability reflecting differences in stage mix and surgical candidacy. ^{25, 30– 33}

The signal was strongest in advanced or restaging settings, consistent with the literature: in higher stages the pre-test probability of spread is greater, the incremental detection of ¹⁸F-FDG PET/CT is larger, and downstream decisions are more likely to change. ¹³ By contrast, in truly early stages without high-risk features, ¹⁸F-FDG PET/CT rarely altered management in this study, which is concordant with published recommendations. ^{12, 13} Taken together, these observations indicate that ¹⁸F-FDG PET/CT acts as an add-on to conventional imaging when results are likely to influence therapeutic planning, and as a replacement whole-body modality in the restaging context where a comprehensive disease map is required for systemic therapy decisions.

The therapeutic context has evolved with the adoption of immunotherapy and BRAF/MEK-targeted therapy as standards. ¹⁸F-FDG PET/CT is most useful before systemic treatment to establish a baseline, document true disease extent, and aid prognostic stratification. ^{34– 37} About 40% of metastatic melanomas harbour BRAF V600; early metabolic response on PET can separate prognostic groups under BRAF inhibition, with more homogeneous early decline in uptake associated with longer time to progression. ^{38, 39} When BRAF V600 is absent, adjuvant pembrolizumab improves distant metastasis-free and relapse-free survival in resected stage III melanoma, and pre-therapeutic ¹⁸F-FDG PET/CT helps exclude occult stage IV disease before adjuvant therapy is started. ^{40, 41} In our cohort, ¹⁸F-FDG PET/CT supported initiation, continuation, addition, or avoidance of immunotherapy according to the disease map it provided. Under immunotherapy, ¹⁸F-FDG PET/CT may display atypical patterns like pseudoprogression, hyperprogression, or dissociated responses. These particular aspects can confound conventional criteria. Immune-adapted frameworks (imRECIST for CT and iPERCIST for PET) help distinguish true progression from inflammatory flare or mixed response and guide more appropriate decisions. ^{42– 44}

¹⁸F-FDG PET/CT also depicts immune-related adverse events, prompting timely holds or targeted work-up when indicated. ⁴⁵ These imaging nuances strengthen the link between accurate disease characterization and tailored therapy observed in this study.

Finally, emerging tools point to future refinements. Pre-treatment metabolic tumour volume on FDG PET carries independent prognostic value in patients receiving immune checkpoint inhibitors, opening paths for risk-adapted imaging and therapy. ^{46, 47} New tracers, such as the melanin-avid ¹⁸F-N-(2-(Diethylamino)ethyl)-5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy) picolinamide ( ¹⁸F-PFPN), may improve lesion conspicuity and help differentiate inflammatory uptake from melanocytic disease during immunotherapy, though performance may be lower in amelanotic subtypes; these advances were outside the scope of this study but indicate where next-generation staging and response assessment may head. ^{48, 49}

In this study’s setting, and while considering the international recommendations and local care patterns, we favour a context-adapted approach that integrates ¹⁸F-FDG PET/CT selectively and escalating its use when the pre-test probability of metastasis or the likelihood of therapeutic consequence is high and deferring it when expected yield is limited. For non-advanced stages (I-II), no routine ¹⁸F-FDG PET/CT is indicated and SLNB should be considered for stage IB (ulceration or high mitotic index). For stages IIA-IIB, locoregional ultrasound is recommended; if negative, sentinel lymph node biopsy may be undertaken. For advanced stages (IIC-IIIC), locoregional ultrasound and TAP CT are generally recommended, with ¹⁸F-FDG PET/CT considered as an alternative to consolidate staging and inform therapy. For stage IV, ¹⁸F-FDG PET/CT or TAP CT plus brain MRI are generally advised to achieve comprehensive staging prior to definitive systemic or surgical management.

This study has several limitations, notably its retrospective and single-centre nature. Another constraint is the small sample size which is below the idealized target derived from literature-based planning. As a result, confidence intervals were wide in early-stage strata, so estimates, particularly the 100% values, should be interpreted cautiously and validated prospectively. It nonetheless provides interpretable diagnostic accuracy estimates. This could be explained largely by the low incidence of melanoma as well as the recent implementation of ¹⁸F-FDG PET/CT in Tunisia. Another explanation could be the lack of regulatory rule that requires ¹⁸F-FDG PET/CT to prescribe immunotherapy or targeted therapy. In addition, because histopathologists and clinicians assessing the reference standard had access to imaging results, the possibility of review bias cannot be excluded, which may have slightly inflated accuracy estimates. To mitigate these limitations and enhance generalizability, future investigations should adopt a prospective, multi-centre design.

This study results show that ¹⁸F-FDG PET/CT improves detection over CT, explains the observed low inter-modality concordance by identifying additional true disease in an unselected population at advanced and early stages of the disease. Pooled ¹⁸F-FDG PET/CT sensitivity and specificity surpass CT for distant metastases and are higher for nodal disease. These findings align with contemporary evidence and support the judicious integration of ¹⁸F-FDG PET/CT into melanoma care pathways. It enables clinicians to tailor treatment more appropriately, whether that means intensifying therapy for those with unseen metastases or safely de-escalating interventions for those without evidence of spread. This synergy between diagnostic precision and therapeutic decision-making ultimately optimizes patient care, potentially contributing to improved outcomes as suggested in emerging real-world analyses.

This study was conducted in accordance with the ethical standards of the institutional and national research committees. The protocol was approved by the Ethics Committee of Sahloul University Hospital, Faculty of Medicine of Sousse, University of Sousse, Tunisia (Approval No. [HS52-2025]).

Written informed consent was obtained from all participants to participate in the study.

The authors used a generative AI assistant (GPT-5 Thinking, OpenAI) to help translate sections, improve grammar and clarity, and format figures.